1. Field of the Invention
The present invention provides for an efficient method of effecting the resolution of a narwedine amide, and the synthesis of galantamine.
2. Description of the Related Art
Narwedine derivatives have been utilized for the synthesis of (−)galantamine, a natural product derived from Amaryllidaceae species, which has recently been approved as an Alzheimer's drug. Initially this substance was obtained in pure form by extraction from bulbs of Causasian snowdrops but recently (−)galantamine has been shown to be obtained more efficiently by total synthesis. The synthesis of galantamine in either chiral form or achiral form has been the topic of a number of patents and papers.
Galantamine was originally synthesized in optically active form by Barton and Kirby (J. Chem. Soc., 1962(806)) where they demonstrated a resolution by seeding with (+)-galantamine to produce crystals of (−)narwedine which is the precursor to the desired (−)-galantamine by subsequent reduction of the ketone. It was shown that a number of other galantamine derivatives could be used to produce the desired crystallization. In their procedure they employed large amounts of seed crystals. Likewise, U.S. Pat. No. 5,428,159 demonstrates a similar resolution with the use of (−)narwedine as a seed and the use of only 1-2.5% seed equivalence. In either case, an amide had been prepared during the synthesis of the (±) narwedine and this amide was reduced to the free amine prior to the resolution. Therefore, it would be advantageous if an amide precursor could be resolved and the reduction accomplished later in the synthesis.
The synthesis of (±)-galantamine has been previously reported to proceed through the synthesis of bromoamide (I) by the oxidative cyclization of the diphenol (II) (Kametani, et.al., J. Chem. Soc. (C), 2602(1969)). The resolution of this amide has not been reported. One of the apparent difficulties is to obtain a source of seed crystals which contain a similar structure in that this compound is not a natural product. Likewise the change from an amine to an amide would create a different geometry in the molecule and eliminate a source of basic amine useful in the resolution and also create greatly different solubility.